Structure and function of Semaphorin-5A glycosaminoglycan interactions

Gergely N. Nagy (), Xiao-Feng Zhao, Richard Karlsson, Karen Wang, Ramona Duman, Karl Harlos, Kamel El Omari, Armin Wagner, Henrik Clausen, Rebecca L. Miller (), Roman J. Giger () and E. Yvonne Jones ()
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Gergely N. Nagy: University of Oxford
Xiao-Feng Zhao: University of Michigan Medical School
Richard Karlsson: University of Copenhagen
Karen Wang: University of Michigan Medical School
Ramona Duman: Harwell Science and Innovation Campus
Karl Harlos: University of Oxford
Kamel El Omari: Harwell Science and Innovation Campus
Armin Wagner: Harwell Science and Innovation Campus
Henrik Clausen: University of Copenhagen
Rebecca L. Miller: University of Copenhagen
Roman J. Giger: University of Michigan Medical School
E. Yvonne Jones: University of Oxford

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Integration of extracellular signals by neurons is pivotal for brain development, plasticity, and repair. Axon guidance relies on receptor-ligand interactions crosstalking with extracellular matrix components. Semaphorin-5A (Sema5A) is a bifunctional guidance cue exerting attractive and inhibitory effects on neuronal growth through the interaction with heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs), respectively. Sema5A harbors seven thrombospondin type-1 repeats (TSR1-7) important for GAG binding, however the underlying molecular basis and functions in vivo remain enigmatic. Here we dissect the structural basis for Sema5A:GAG specificity and demonstrate the functional significance of this interaction in vivo. Using x-ray crystallography, we reveal a dimeric fold variation for TSR4 that accommodates GAG interactions. TSR4 co-crystal structures identify binding residues validated by site-directed mutagenesis. In vitro and cell-based assays uncover specific GAG epitopes necessary for TSR association. We demonstrate that HS-GAG binding is preferred over CS-GAG and mediates Sema5A oligomerization. In vivo, Sema5A:GAG interactions are necessary for Sema5A function and regulate Plexin-A2 dependent dentate progenitor cell migration. Our study rationalizes Sema5A associated developmental and neurological disorders and provides mechanistic insights into how multifaceted guidance functions of a single transmembrane cue are regulated by proteoglycans.

Date: 2024
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DOI: 10.1038/s41467-024-46725-7

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